Diabetic nephropathy (DN) is the most serious long-term complication of diabetes, accounting for about 35% of all new cases of end-stage renal disease in the U.S. Two lines of evidence suggest a strong genetic component in susceptibility to diabetic kidney disease: (1) the prevalence of DN increases during the first 15 to 20 years of diabetes, then reaches a plateau; (2) family studies show a distinct pattern of clustering of DN; diabetic sibs of probands with DN have a significantly greater risk for developing kidney complications than do sibs of probands without DN. We propose to (1) determine whether DN is genetically linked to any of a set of proposed candidate genes whose function in the kidney suggests a role in genetic susceptibility, and (2) use microarray technology to identify genes that differentially expressed in the kidneys of diabetics with and without DN. cDNAs for candidate genes, as well as random clones from kidney cDNA library, will be screened. Previously identified candidate genes, and other known genes that were not considered candidates, will be identified by this test for differential expression. It is also possible that previously unknown genes will be identified in this way. All of these genes will be given high priority and extra scrutiny in the tests for linkage with DN. Using sequence information of each of these genes and nearby regions, polymorphisms in and near the genes will be identified. To test for linkage, we are assembling a panel of families that have several members with diabetic nephropathy, or are otherwise suitable for linkage analysis. Tests will be carried out for linkage disequilibrium (using the transmission/disequilibrium test, TDT) and where possible, affected sib pair and other sib pair test methods.